Targeted resequencing identifies genes with recurrent variation in cerebral palsy

Eyk, Clare L. van; Corbett, Mark; Frank, Mahalia S. B.; Webber, Dani L.; Newman, Morgan; Berry, Jesia G.; Harper, Kelly; Haines, Bryan P.; McMichael, G.; Woenig, Joshua A.; MacLennan, Alastair H.; Gécz, Jozef

doi:10.1038/s41525-019-0101-z

Cited by 24 publications

(25 citation statements)

References 61 publications

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“…TUBA1A missense variants, for example, can have subtle effects on microtubule shape and protein interactions, which may contribute to considerable phenotype heterogeneity ( 34 ). Even in some cases where genes have been shown to have an essential role in movement in model organism studies using zebrafish or Drosophila, the human variants were not tested to confirm variant-specific effects ( 21 , 35 ).…”

Section: What Constitutes a Cp-associated Gene?mentioning

confidence: 99%

Insights From Genetic Studies of Cerebral Palsy

et al. 2021

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Cohort-based whole exome and whole genome sequencing and copy number variant (CNV) studies have identified genetic etiologies for a sizable proportion of patients with cerebral palsy (CP). These findings indicate that genetic mutations collectively comprise an important cause of CP. We review findings in CP genomics and propose criteria for CP-associated genes at the level of gene discovery, research study, and clinical application. We review the published literature and report 18 genes and 5 CNVs from genomics studies with strong evidence of for the pathophysiology of CP. CP-associated genes often disrupt early brain developmental programming or predispose individuals to known environmental risk factors. We discuss the overlap of CP-associated genes with other neurodevelopmental disorders and related movement disorders. We revisit diagnostic criteria for CP and discuss how identification of genetic etiologies does not preclude CP as an appropriate diagnosis. The identification of genetic etiologies improves our understanding of the neurobiology of CP, providing opportunities to study CP pathogenesis and develop mechanism-based interventions.

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Section: What Constitutes a Cp-associated Gene?mentioning

confidence: 99%

Insights From Genetic Studies of Cerebral Palsy

et al. 2021

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“…Also in 2015, the first WES study in a cohort of 201 CP cases demonstrated an important contribution of single nucleotide variants (SNVs), with a diagnostic yield of 14% (25). Another study in 2018 even reached a diagnostic yield of 65% using WES in 50 individuals with atypical CP; however, this study also included promising candidate genes whose role in CP has not been validated (26). A study in 2019, using a gene panel of 112 genes consisting of a combination of known disease genes and candidate genes classified as intolerant to variation, found genetic variants of possible clinical relevance in 10% of the CP cohort (27).…”

Section: Discussionmentioning

confidence: 99%

“…Another study in 2018 even reached a diagnostic yield of 65% using WES in 50 individuals with atypical CP; however, this study also included promising candidate genes whose role in CP has not been validated ( 26 ). A study in 2019, using a gene panel of 112 genes consisting of a combination of known disease genes and candidate genes classified as intolerant to variation, found genetic variants of possible clinical relevance in 10% of the CP cohort ( 27 ). While the genetic causes are heterogeneous, this study identified six recurrent genes that contributed to at least 4% of disease burden in CP: COL4A1, TUBA1A, AGAP1, L1CAM, MAOB and KIF1A ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

“…A study in 2019, using a gene panel of 112 genes consisting of a combination of known disease genes and candidate genes classified as intolerant to variation, found genetic variants of possible clinical relevance in 10% of the CP cohort ( 27 ). While the genetic causes are heterogeneous, this study identified six recurrent genes that contributed to at least 4% of disease burden in CP: COL4A1, TUBA1A, AGAP1, L1CAM, MAOB and KIF1A ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

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Genetic Testing Contributes to Diagnosis in Cerebral Palsy: Aicardi-Goutières Syndrome as an Example

et al. 2021

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Cerebral palsy (CP) is a non-progressive neurodevelopmental disorder characterized by motor impairments, often accompanied by co-morbidities such as intellectual disability, epilepsy, visual and hearing impairment and speech and language deficits. Despite the established role of hypoxic–ischemic injury in some CP cases, several studies suggest that birth asphyxia is actually an uncommon cause, accounting for <10% of CP cases. For children with CP in the absence of traditional risk factors, a genetic basis to their condition is increasingly suspected. Several recent studies indeed confirm copy number variants and single gene mutations with large genetic heterogeneity as an etiology in children with CP. Here, we report three patients with spastic cerebral palsy and a genetically confirmed diagnosis of Aicardi-Goutières syndrome (AGS), with highly variable phenotypes ranging from clinically suggestive to non-specific symptomatology. Our findings suggest that AGS may be a rather common cause of CP, that frequently remains undiagnosed without additional genetic testing, as in only one case a clinical suspicion of AGS was raised. Our data show that a diagnosis of AGS must be considered in cases with spastic CP, even in the absence of characteristic brain abnormalities. Importantly, a genetic diagnosis of AGS may have significant therapeutic consequences, as targeted therapies are being developed for type 1 interferonopathies, the group of diseases to which AGS belongs. Our findings demonstrate the importance of next generation sequencing in CP patients without an identifiable cause, since targeted diagnostic testing is hampered by the often non-specific presentation.

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“…Genetic analyses performed in CP cohorts showed a monogenic cause in ~5% ( 27 ) to 15% ( 22 ) of cases, vastly differing between different subgroups. This factor may increase during the next years when comprehensive genetic analysis such as whole-genome sequencing (WGS) will be more broadly available and more CP genes presumably identified.…”

Section: Introductionmentioning

confidence: 99%

The Role of Neuroimaging and Genetic Analysis in the Diagnosis of Children With Cerebral Palsy

Horber

Grasshoff²,

Sellier

et al. 2021

Front. Neurol.

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Cerebral magnetic resonance imaging (MRI) is considered an important tool in the assessment of a child with cerebral palsy (CP), as it is abnormal in more than 80% of children with CP, disclosing the pathogenic pattern responsible for the neurological condition. MRI, therefore, is recommended as the first diagnostic step after medical history taking and neurological examination. With the advances in genetic diagnostics, the genetic contribution to CP is increasingly discussed, and the question arises about the role of genetic testing in the diagnosis of cerebral palsy. The paper gives an overview on genetic findings reported in CP, which are discussed with respect to the underlying brain pathology according to neuroimaging findings. Surveillance of Cerebral Palsy in Europe (SCPE) classifies neuroimaging findings in CP into five categories, which help to stratify decisions concerning genetic testing. Predominant white and gray matter injuries are by far predominant (accounting for around 50 and 20% of the findings). They are considered to be acquired. Here, predisposing genetic factors may play a role to increase vulnerability (and should especially be considered, when family history is positive and/or causative external factors are missing). In maldevelopments and normal findings (around 11% each), monogenic causes are more likely, and thus, genetic testing is clearly recommended. In the miscellaneous category, the precise nature of the MRI finding has to be considered as it could indicate a genetic origin.

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Targeted resequencing identifies genes with recurrent variation in cerebral palsy

Cited by 24 publications

References 61 publications

Insights From Genetic Studies of Cerebral Palsy

Insights From Genetic Studies of Cerebral Palsy

Genetic Testing Contributes to Diagnosis in Cerebral Palsy: Aicardi-Goutières Syndrome as an Example

The Role of Neuroimaging and Genetic Analysis in the Diagnosis of Children With Cerebral Palsy

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